Thursday, Aug. 14, 2008 | In a laboratory at the La Jolla-based Salk Institute nearly 10 years ago, researcher Rusty Gage established that new brain cells can be grown in the human brain, a finding that reversed accepted dogma and left researchers hoping to eventually transform the way mood disorders are treated.
The process, known as neurogenesis, spurs stem cells in the adult brain to produce a fresh supply of brain cells; such growth usually declines in early adulthood.
Then, in 2003, a colleague had another breakthrough: Rene Hen, a Columbia University neuroscientist, posited that it was this process — not pharmaceutical drugs — that seemed to be improving the mood of mice in early research on depression.
They were so encouraged by the findings that later that year, Gage and Hen founded BrainCells Inc. The small San Diego firm today has one brain cell-boosting drug in mid-stage human clinical trial for depression and anxiety and it hopes to eventually ease many of the serious side affects that come with traditional antidepressants such as Prozac and Zoloft.
And while many questions remain about the link between mood disorders and neurogenesis, BrainCells has managed to secure an impressive $77 million from investors at a time when venture capital is scarce. The company’s goal is to identify and retool existing drugs — some of which have floundered in their original purposes — into new drugs that can treat mood disorders.
“If your parents ever told you that you were wasting brain cells you could never get back, they were wrong,” said Carrolee Barlow, a neuroscientist who left Merck to become the fledgling company’s chief scientific officer. “You can get some of them back.”
Most antidepressants have been assumed to work by correcting an imbalance in the brain. The drugs increase the available supply of serotonin, a chemical that influences mood in the brain. But Gage’s and Hen’s findings instigated a paradigm shift in psychiatry. If neurogenesis, instead of serotonin, is key to treating mood disorders, other drugs may also have the ability to trigger the process, researchers at BrainCells said.
Dozens of antidepressant drugs are on the market, but psychiatrists largely agree there is a need for new ones, mostly because the drugs routinely prescribed are very similar and are delivered via serotonin pathways in the brain, leaving few options if patients don’t feel better with the drugs. Roughly one-third of patients with depression are resistant to antidepressant treatments, and close to 15 percent of patients switch drugs because of side effects, such as sexual dysfunction, insomnia, anxiety, and gastrointestinal problems, according to statistics from the psychiatry department of the University of California, San Diego.
While a new supply of brain cells appears in early tests to be effective in treating mood disorders, even scientists intimately involved in the research aren’t sure why, partly because the study of neurogenesis is so new.
The company uses a strategy known as piggybacking. It’s not trying to produce its own new drugs in-house. Rather, it is testing already existing drugs to see if they are able to trigger neurogenesis.
Because the majority of drugs that are on the market or have been tested in clinical trials have never been screened for that ability, BrainCells has, since 2004, screened nearly 1,000 existing drugs to see which ones stimulate the process, and therefore might make good antidepressants with fewer side effects.
Screenings are done by mixing the drugs with human stem cells in a test tube to find out which ones cause stem cells to form brain cells more quickly. When a drug appears promising, it’s applied to a sheet of stem cells that are grown in an incubator in BrainCells’ lab. If the stem cells proliferate and transform into brain cells, it means it could serve as an alternative to antidepressants.
After testing 539 drugs on countless stem cells in a Petri dish, researchers found a brain cell-boosting drug they refer to as BCI 540 because it was the 540th one screened by BrainCells Inc., said Todd Carter, the company’s director of biology.
The drug “worked beautifully in a dish,” he said. “Now we’ll see how it works outside of it.”
The drug is in clinical human trials now and Carter said the data should be ready for review by next year. But since scientists don’t know what in the brain specifically leads to depression, a lot of questions remain about whether neurogenesis alone could be an effective therapy. More uncertainties center on the question of whether the process could induce the growth of enough new neurons to eradicate the need for antidepressants altogether.
“Can we eliminate the need for drugs altogether if enough neurons are regrown? Can we change the milieu of the brain?” Kai Treuner, a company research scientist said. “I don’t know. It’s too soon to tell.”
Disclosing the identity of the drug or how it works would be tantamount to giving away trade secrets, BrainCells executives said, but the drug appears to primarily affect neurons’ capacity to survive and become integrated into the brain’s pathways. The drug uses a pathway, or circuit, in the brain that is unrelated to serotonin and offers a “straight shot” to neurons, Barlow said.
The findings are promising, and the idea of modifying existing drugs for new uses is a rich field in biotech, but moving research out of the lab and into human trials often yields disappointing results. According to the Food and Drug Administration, of every 5,000 medicines tested, only five on average make it to clinical trials — a hurdle BrainCells’ drug has already overcome — and only one of those is eventually approved for human use. Also, since rats and mice are imperfect models for human mood disorders, researchers have to rely on tests that merely approximate behavior that is part of depression in people.
Nonetheless, investors so far have been confident enough in the company’s prospects to back the research with nearly $80 million. While other fledgling companies in San Diego are struggling to secure funding, several industry insiders said BrainCells’ piggyback approach to finding new drugs may help make it profitable.
By choosing drugs that have already passed safety trials, the firm could significantly truncate lengthy drug development timelines and save millions of investors’ dollars, ultimately getting the therapy to patients quicker.
The approach requires leasing drugs from companies, which can be a difficult process. Before BCI 540 emerged in BrainCells’ screens, several other drugs showed promising results. Barlow said she approached a handful of companies to begin negotiations to lease the rights to use their drugs, but when BrainCells presented the neurogenesis data from the potential drug, they declined to turn over the compound, she said.
“Once companies discover that their compound might have useful properties, they’re not likely to be willing to give it away,” Barlow said.
BrainCells was able to lease the drug now in clinical trials from Mitsubishi Pharma. If the company can prove in trials that the drug alone is effective in changing the mood of depressed patients, Barlow said the firm will work with a large pharmaceutical company to develop a new antidepressant, a process that would take many years.
“Trials are going well,” Carter, the biology director, said. “We’re hoping to find that patients are happier today than they were yesterday, thanks to the drug,”
This article relates to: Science